Prediction of resting energy expenditure for adolescents with severe obesity: A multi-centre analysis.

BACKGROUND AND OBJECTIVES: Resting energy expenditure (REE) assessments can help inform clinical treatment decisions in adolescents with elevated body mass index (BMI), but current equations are suboptimal for severe obesity. We developed a predictive REE equation for youth with severe obesity and obesity-related comorbidities and compared results to previously published predictive equations. METHODS: Data from indirect calorimetry, clinical measures, and body composition per Dual x-ray absorptiometry (DXA) were collected from five sites. Data were randomly divided into development (N = 438) and validation (N = 118) cohorts. A predictive equation was developed using Elastic Net regression, using sex, race, ethnicity, weight, height, BMI percent of the 95th%ile (BMIp95), waist circumference, hip circumference, waist/hip ratio, age, Tanner stage, fat and fat-free mass. This equation was verified in the validation cohort and compared with 11 prior equations. RESULTS: Data from the total cohort (n = 556, age 15 ± 1.7 years, 77% female, BMIp95 3.3 ± 0.94) were utilized. The best fit equation was REE = -2048 + 18.17 × (Height in cm) - 2.57 × (Weight in kg) + 7.88 × (BMIp95) + 189 × (1 = male, 0 = female), R2 = 0.466, and mean bias of 23 kcal/day. CONCLUSION: This new equation provides an updated REE prediction that accounts for severe obesity and metabolic complications frequently observed in contemporary youth.

Comprehensive transition of care for polycystic ovary syndrome from adolescence to adulthood.

Polycystic ovary syndrome (PCOS) is a lifelong chronic condition that affects one in ten females and can be diagnosed in adolescence. As adolescents with PCOS transition to adulthood, counselling for lifestyle management and mental health concerns often transition from involving the family unit to increasingly individual-focused approaches. PCOS is associated with a large range of comorbidities affecting reproductive, metabolic, dermatological, and psychological health. The diagnosis and comorbidities of PCOS are influenced by pubertal hormones and need to be reassessed continuously to ensure that treatment remains appropriate for age and development. As young patients grow up, personal concerns often change, especially in relation to reproductive management. In this Review, we present prevalence rates, screening tools, and treatment recommendations for PCOS-related conditions, and we consider the diagnostic and clinical elements of optimal transition of care models that ensure continuity of comprehensive care for adolescents moving from the paediatric health-care system to the adult health-care system.

Metabolic effects of an essential amino acid supplement in adolescents with PCOS and obesity.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, insulin resistance, and hepatic steatosis (HS). Because dietary essential amino acid (EAA) supplementation has been shown to decrease HS in various populations, this study's objective was to determine whether supplementation would decrease HS in PCOS. METHODS: A randomized, double-blind, crossover, placebo-controlled trial was conducted in 21 adolescents with PCOS (BMI 37.3 ± 6.5 kg/m2, age 15.6 ± 1.3 years). Liver fat, very low-density lipoprotein (VLDL) lipogenesis, and triacylglycerol (TG) metabolism were measured following each 28-day phase of placebo or EAA. RESULTS: Compared to placebo, EAA was associated with no difference in body weight (p = 0.673). Two markers of liver health improved: HS was lower (-0.8% absolute, -7.5% relative reduction, p = 0.013), as was plasma aspartate aminotransferase (AST) (-8%, p = 0.004). Plasma TG (-9%, p = 0.015) and VLDL-TG (-21%, p = 0.031) were reduced as well. VLDL-TG palmitate derived from lipogenesis was not different between the phases, nor was insulin sensitivity (p > 0.400 for both). Surprisingly, during the EAA phase, participants reported consuming fewer carbohydrates (p = 0.038) and total sugars (p = 0.046). CONCLUSIONS: Similar to studies in older adults, short-term EAA supplementation in adolescents resulted in significantly lower liver fat, AST, and plasma lipids and thus may prove to be an effective treatment in this population. Additional research is needed to elucidate the mechanisms for these effects.

Distinct Reproductive Phenotypes Segregate With Differences in Body Weight in Adolescent Polycystic Ovary Syndrome.

Introduction: Polycystic ovary syndrome (PCOS) is a heterogenous clinical syndrome defined by hyperandrogenism and irregular menses. In adult women with PCOS, discrete metabolic and reproductive subgroups have been identified. We hypothesize that distinct phenotypes can be distinguished between adolescent girls who are lean (LN-G) and girls with obesity (OB-G) at the time of PCOS diagnosis. Methods: Data were extracted from the CALICO multisite PCOS database. Clinical data collected at the time of diagnosis were available in 354 patients (81% with obesity) from 7 academic centers. Patients with body mass index (BMI) < 85th percentile for age and sex were characterized as lean (LN-G) and those with BMI percentile ≥ 95th percentile as obese (OB-G). We compared metabolic and reproductive phenotypes in LN-G and OB-G. Results: Reproductive phenotypes differed between the groups, with LN-G having higher total testosterone, androstenedione, and LH levels, while OB-G had lower sex hormone binding globulin (SHBG) and higher free testosterone. Metabolic profiles differed as expected, with OB-G having higher hemoglobin A1c, alanine aminotransferase, and serum triglycerides and more severe acanthosis nigricans. Conclusion: LN-G with PCOS had a distinct reproductive phenotype characterized by increased LH, total testosterone, and androstenedione levels, suggesting neuroendocrine-mediated ovarian androgen production. In contrast, phenotypes in OB-G suggest hyperandrogenemia is primarily driven by insulin resistance with low SHBG levels. These observations support the existence of distinct metabolic and reproductive subtypes in adolescent PCOS characterized by unique mechanisms for hyperandrogenemia.

Estimating Insulin Sensitivity and Beta-Cell Function from the Oral Glucose Tolerance Test: Validation of a new Insulin Sensitivity and Secretion (ISS) Model.

Efficient and accurate methods to estimate insulin sensitivity (SI) and beta-cell function (BCF) are of great importance for studying the pathogenesis and treatment effectiveness of type 2 diabetes. Existing methods range in sensitivity, input data and technical requirements. Oral glucose tolerance tests (OGTTs) are preferred because they are simpler and more physiological than intravenous methods. However, current analytical methods for OGTT-derived SI and BCF also range in complexity; the oral minimal models require mathematical expertise for deconvolution and fitting differential equations, and simple algebraic surrogate indices (e.g., Matsuda index, insulinogenic index) may produce unphysiological values. We developed a new ISS (Insulin Secretion and Sensitivity) model for clinical research that provides precise and accurate estimates of SI and BCF from a standard OGTT, focusing on effectiveness, ease of implementation, and pragmatism. The model was developed by fitting a pair of differential equations to glucose and insulin without need of deconvolution or C-peptide data. The model is derived from a published model for longitudinal simulation of T2D progression that represents glucose-insulin homeostasis, including post-challenge suppression of hepatic glucose production and first- and second-phase insulin secretion. The ISS model was evaluated in three diverse cohorts across the lifespan. The new model had strong correlation with gold-standard estimates from intravenous glucose tolerance tests and insulin clamps. The ISS model has broad applicability among diverse populations because it balances performance, fidelity, and complexity to provide a reliable phenotype of T2D risk.

Estimating Insulin Sensitivity and Beta-Cell Function from the Oral Glucose Tolerance Test: Validation of a new Insulin Sensitivity and Secretion (ISS) Model.

Efficient and accurate methods to estimate insulin sensitivity (SI) and beta-cell function (BCF) are of great importance for studying the pathogenesis and treatment effectiveness of type 2 diabetes. Many methods exist, ranging in input data and technical requirements. Oral glucose tolerance tests (OGTTs) are preferred because they are simpler and more physiological. However, current analytical methods for OGTT-derived SI and BCF also range in complexity; the oral minimal models require mathematical expertise for deconvolution and fitting differential equations, and simple algebraic models (e.g., Matsuda index, insulinogenic index) may produce unphysiological values. We developed a new ISS (Insulin Secretion and Sensitivity) model for clinical research that provides precise and accurate estimates of SI and BCF from a standard OGTT, focusing on effectiveness, ease of implementation, and pragmatism. The model was developed by fitting a pair of differential equations to glucose and insulin without need of deconvolution or C-peptide data. The model is derived from a published model for longitudinal simulation of T2D progression that represents glucose-insulin homeostasis, including post-challenge suppression of hepatic glucose production and first- and second-phase insulin secretion. The ISS model was evaluated in three diverse cohorts including individuals at high risk of prediabetes (adult women with a wide range of BMI and adolescents with obesity). The new model had strong correlation with gold-standard estimates from intravenous glucose tolerance tests and hyperinsulinemic-euglycemic clamp. The ISS model has broad clinical applicability among diverse populations because it balances performance, fidelity, and complexity to provide a reliable phenotype of T2D risk.

Glycerol as a precursor for hepatic de novo glutathione synthesis in human liver.

BACKGROUND: Glycerol is a substrate for gluconeogenesis and fatty acid esterification in the liver, processes which are upregulated in obesity and may contribute to excess fat accumulation. Glycine and glutamate, in addition to cysteine, are components of glutathione, the major antioxidant in the liver. In principle, glycerol could be incorporated into glutathione via the TCA cycle or 3-phosphoglycerate, but it is unknown whether glycerol contributes to hepatic de novo glutathione biosynthesis. METHODS: Glycerol metabolism to hepatic metabolic products including glutathione was examined in the liver from adolescents undergoing bariatric surgery. Participants received oral [U-13C3]glycerol (50 mg/kg) prior to surgery and liver tissue (0.2-0.7g) was obtained during surgery. Glutathione, amino acids, and other water-soluble metabolites were extracted from the liver tissue and isotopomers were quantified with nuclear magnetic resonance spectroscopy. RESULTS: Data were collected from 8 participants (2 male, 6 female; age 17.1 years [range 14-19]; BMI 47.4 kg/m2 [range 41.3-63.3]). The concentrations of free glutamate, cysteine, and glycine were similar among participants, and so were the fractions of 13C-labeled glutamate and glycine derived from [U-13C3]glycerol. The signals from all component amino acids of glutathione - glutamate, cysteine and glycine - were strong and analyzed to obtain the relative concentrations of the antioxidant in the liver. The signals from glutathione containing [13C2]glycine or [13C2]glutamate derived from the [U-13C3]glycerol drink were readily detected, and 13C-labelling patterns in the moieties were consistent with the patterns in corresponding free amino acids from the de novo glutathione synthesis pathway. The newly synthesized glutathione with [U-13C3]glycerol trended to be lower in obese adolescents with liver pathology. CONCLUSIONS: This is the first report of glycerol incorporation into glutathione through glycine or glutamate metabolism in human liver. This could represent a compensatory mechanism to increase glutathione in the setting of excess glycerol delivery to the liver.

Impaired glucose tolerance in pediatric burn patients at discharge from the acute hospital stay.

Hyperglycemia, secondary to the hypermetabolic stress response, is a common occurrence after thermal injury. This stress response has been documented to persist up to 9 months postburn. The purpose of this study was to measure insulin sensitivity in severely burned children before discharge when wounds are 95% healed. Twenty-four children, aged 4 to 17 years, with burns > or = 40% TBSA underwent a 2-hour oral glucose tolerance test before discharge from the acute pediatric burn unit. Plasma glucose and insulin levels as well as the Homeostasis Model Assessment for Insulin Resistance (HOMAIR) were compared with published oral glucose tolerance test data from healthy, nonburned children. There was a significant difference between severely burned children and nonburned, healthy children with respect to the HOMAIR. Severely burned children had a HOMAIR of 3.53 +/- 1.62 compared with the value in nonburned, healthy children of 1.28 +/- 0.16 (P < .05). Insulin resistance secondary to the hypermetabolic stress response persists in severely burned children when burn wounds are at least 95% healed. The results of this study warrant future investigations into therapeutic options for the burned child during the rehabilitative phase of their care after injury.

Metabolic profiling of muscle contraction in lean compared with obese rodents.

Interest in the pathophysiological relevance of intramuscular triacylglycerol (IMTG) accumulation has grown from numerous studies reporting that abnormally high glycerolipid levels in tissues of obese and diabetic subjects correlate negatively with glucose tolerance. Here, we used a hindlimb perfusion model to examine the impact of obesity and elevated IMTG levels on contraction-induced changes in skeletal muscle fuel metabolism. Comprehensive lipid profiling was performed on gastrocnemius muscles harvested from lean and obese Zucker rats immediately and 25 min after 15 min of one-legged electrically stimulated contraction compared with the contralateral control (rested) limbs. Predictably, IMTG content was grossly elevated in control muscles from obese rats compared with their lean counterparts. In muscles of obese (but not lean) rats, contraction resulted in marked hydrolysis of IMTG, which was then restored to near resting levels during 25 min of recovery. Despite dramatic phenotypical differences in contraction-induced IMTG turnover, muscle levels of diacylglycerol (DAG) and long-chain acyl-CoAs (LCACoA) were surprisingly similar between groups. Tissue profiles of acylcarnitine metabolites suggested that the surfeit of IMTG in obese rats fueled higher rates of fat oxidation relative to the lean group. Muscles of the obese rats had reduced lactate levels immediately following contraction and higher glycogen resynthesis during recovery, consistent with a lipid-associated glucose-sparing effect. Together, these findings suggest that contraction-induced mobilization of local lipid reserves in obese muscles promotes beta-oxidation, while discouraging glucose utilization. Further studies are necessary to determine whether persistent oxidation of IMTG-derived fatty acids contributes to systemic glucose intolerance in other physiological settings.

Intensive insulin therapy improves insulin sensitivity and mitochondrial function in severely burned children.

OBJECTIVE: To institute intensive insulin therapy protocol in an acute pediatric burn unit and study the mechanisms underlying its benefits. DESIGN: Prospective, randomized study. SETTING: An acute pediatric burn unit in a tertiary teaching hospital. PATIENTS: Children, 4-18 yrs old, with total body surface area burned > or =40% and who arrived within 1 wk after injury were enrolled in the study. INTERVENTIONS: Patients were randomized to one of two groups. Intensive insulin therapy maintained blood glucose levels between 80 and 110 mg/dL. Conventional insulin therapy maintained blood glucose < or =215 mg/dL. MEASUREMENTS AND MAIN RESULTS: Twenty patients were included in the data analysis consisting of resting energy expenditure, whole body and liver insulin sensitivity, and skeletal muscle mitochondrial function. Studies were performed at 7 days postburn (pretreatment) and at 21 days postburn (posttreatment). Resting energy expenditure significantly increased posttreatment (1476 +/- 124 to 1925 +/- 291 kcal/m(2) x day; p = .02) in conventional insulin therapy as compared with a decline in intensive insulin therapy. Glucose infusion rate was identical between groups before treatment (6.0 +/- 0.8 conventional insulin therapy vs. 6.8 +/- 0.9 mg/kg x min intensive insulin therapy; p = .5). Intensive insulin therapy displayed a significantly higher glucose clamp infusion rate posttreatment (9.1 +/- 1.3 intensive insulin therapy versus 4.8 +/- 0.6 mg/kg x min conventional insulin therapy, p = .005). Suppression of hepatic glucose release was significantly greater in the intensive insulin therapy after treatment compared with conventional insulin therapy (5.0 +/- 0.9 vs. 2.5 +/- 0.6 mg/kg x min; intensive insulin therapy vs. conventional insulin therapy; p = .03). States 3 and 4 mitochondrial oxidation of palmitate significantly improved in intensive insulin therapy (0.9 +/- 0.1 to 1.7 +/- 0.1 microm O(2)/CS/mg protein/min for state 3, p = .004; and 0.7 +/- 0.1 to 1.3 +/- 0.1 microm O(2)/CS/mg protein/min for state 4, p < .002), whereas conventional insulin therapy remained at the same level of activity (0.9 +/- 0.1 to 0.8 +/- 0.1 microm O(2)/CS/mg protein/min for state 3, p = .4; 0.6 +/- 0.03 to 0.7 +/- 0.1 microm O(2)/CS/mg protein/min, p = .6). CONCLUSION: Controlling blood glucose levels < or =120 mg/dL using an intensive insulin therapy protocol improves insulin sensitivity and mitochondrial oxidative capacity while decreasing resting energy expenditure in severely burned children.

Twenty-eight-day bed rest with hypercortisolemia induces peripheral insulin resistance and increases intramuscular triglycerides.

Spaceflight represents a unique physiologic challenge to humans, altering hormonal profiles and tissue insulin sensitivity. Among these hormonal alterations, hypercortisolemia and insulin insensitivity are thought to negatively affect muscle mass and function with spaceflight. As insulin sensitivity influences the accumulation of muscle triglycerides, we examined this relationship during hypercortisolemia and inactivity. Six young healthy volunteers were confined to bed rest for 28 days. To mimic the stress response observed during spaceflight, hypercortisolemia (20-24 mg/dL) was induced and maintained by oral ingestion of hydrocortisone. On days 1 and 28 of bed rest, insulin sensitivity across the leg was assessed with a local (femoral arterial insulin infusion) 2-stage hyperinsulinemic-euglycemic clamp (stage 1, 35 microU/min per milliliter of leg; stage 2, 70 microU/min per milliliter of leg). Intramuscular lipid was measured with magnetic resonance spectroscopy. After bed rest, there was a decrease in insulin sensitivity, as assessed by glucose uptake during hyperinsulinemia (from 9.1 +/- 1.3 [mean +/- SEM] to 5.2 +/- 0.7 mg/kg of leg per minute [P = .015]). Intramuscular triglyceride increased from 0.077 +/- 0.011 to 0.136 +/- 0.018 (signal area of fat/signal area of standard, P = .009). Intramuscular lipid content correlated with the glucose uptake at day 28 (R = -0.85, P = .035). These data demonstrate that muscular inactivity and hypercortisolemia are associated with an increase in intramuscular triglyceride and skeletal muscle insulin resistance in previously healthy subjects.

Muscle protein synthesis and balance responsiveness to essential amino acids ingestion in the presence of elevated plasma free fatty acid concentrations.

CONTEXT: Elevated plasma free fatty acid (FFA) concentrations are observed under various clinical circumstances and are associated with impaired glucose disposal in skeletal muscle. OBJECTIVE: The aim of the study was to determine the effects of elevated plasma FFA concentrations on the response of protein synthesis and balance in muscle after essential amino acids (EAAs) ingestion. DESIGN: Leg protein kinetics were determined in young healthy individuals before and after the ingestion of EAAs at 10 h after the initiation of either lipid (Liposyn/heparin+EAA) or saline (saline+EAA) infusions. RESULTS: Plasma insulin responses where higher (P <0.05) in the Liposyn/heparin+EAA group than the saline+EAA group both before (14 +/- 4 vs. 6 +/- 1 microIU . ml(-1)) and after (1038 +/- 257 vs. 280 +/- 87 microIU . ml(-1) . 210 min(-1)) the EAA ingestion. After the EAA ingestion, the rates of both leg phenylalanine disappearance (Rd; nmol . min(-1) . kg lean leg mass(-1)) and muscle proteins fractional synthesis (FSR; % . h(-1)) increased (P <0.05) in both the Liposyn/heparin+EAA and saline+EAA groups, but these changes were not different between the two groups (Rd, 102 +/- 32 vs. 118 +/- 34; FSR, 0.014 +/- 0.005 vs. 0.018 +/- 0.007; P > 0.05). Although the leg phenylalanine rate of appearance (Ra; nmol . min(-1) . kg lean leg mass(-1)) was lower (381 +/- 47 vs. 518 +/- 40) and the balance was greater (-109 +/- 20 vs. -172 +/- 17) in the Liposyn/heparin+EAA group compared to the saline+EAA group before the EAA ingestion (P <0.05), the changes in both of these parameters were not different between groups after the EAA ingestion (P > 0.05). CONCLUSIONS: Elevated plasma FFA concentrations do not interfere with the response of muscle protein synthesis and balance to a bolus ingestion of EAAs.

Amino acid supplementation decreases plasma and liver triacylglycerols in elderly.

OBJECTIVE: Hypertriglyceridemia is a risk factor for coronary heart disease. The aim of this study was to determine the effect of amino acid (AA) supplementation on plasma, liver, and muscle lipid concentrations and insulin sensitivity in the elderly. METHODS: Twelve impaired glucose tolerant elderly (mean +/- SD 67.0 +/- 5.6 y of age, seven women and five men) ingested 11 g of essential AAs plus arginine twice a day for 16 wk, after a 7-wk control run-in. Diet and activity were not otherwise modified. Plasma lipid concentrations and oral glucose tolerance were measured every fourth week and tissue lipid concentrations (magnetic resonance spectroscopy) every eighth week. RESULTS: No changes in plasma lipids were observed during the control run-in. AA supplementation lowered plasma triacylglycerol (TG; P < 0.001), total cholesterol (P = 0.048), and very low-density lipoprotein cholesterol (P < 0.001) concentrations. Plasma TG decreased approximately 20% from the initial value of 1.45 +/- 0.18 mmol/L (mean +/- SE, 128 +/- 16 mg/dL), with the greatest decrease in the subjects starting out with the highest concentrations (r = -0.83). Similarly, liver fat content (liver TG/Intralipid standard) decreased approximately 50% from the initial value of 0.34 +/- 0.06 (P = 0.021, n = 8), with the greatest decrease in the subjects who initially had the highest values (r = -0.86). Intramuscular fat content and insulin sensitivity did not change. CONCLUSION: Diet supplementation with AAs lowers plasma TG, total cholesterol, and very low-density lipoprotein cholesterol concentrations and liver lipid content in impaired glucose tolerant elderly. AA supplementation may have a potential role in the treatment of hypertriglyceridemia or hepatic steatosis.

Insulin resistance, secretion and breakdown are increased 9 months following severe burn injury.

Insulin resistance in the acute burn period has been well described, however, it is unknown if alterations in glucose metabolism persist beyond discharge from the acute injury. To measure the duration of insulin resistance following recovery from the acute burn injury, we performed a prospective cross-sectional study with a standard 2-h oral glucose tolerance test in 46 severely burned children at 6, 9 or 12 months following initial injury. Glucose uptake and insulin secretion were assessed following the glucose load. Results were compared to those previously published in healthy children. At 6 months after burn, the 2-h glucose concentration was significantly (P<0.001) greater than controls, and the area under the curve (AUC) of glucose was significantly higher compared to 12 months and to healthy children (P=0.027 and P<0.001, respectively). The 9-month AUC glucose was higher than controls (P<0.01). The 6-month 2-h insulin was significantly higher than controls, as was the AUC of insulin in all time points post-burn. The AUC of C-peptide was significantly greater at 6 months after injury compared to 9 and 12 months (P<0.01 for both). Increased 2h and AUC glucose and insulin indicate that glucose metabolism is still affected at 6 and 9 months after injury, and coincides with previously documented defects in bone and muscle metabolism at these time points. Insulin breakdown is also still increased in this population. Further study of this population is warranted to determine if specific treatment is needed.

Human mitochondrial oxidative capacity is acutely impaired after burn trauma.

BACKGROUND: Mitochondrial proteins and genes are damaged after burn injury in animals and are assessed in human burn patients in this study. METHODS: The rates of maximal muscle mitochondrial oxidative capacity (adenosine triphosphate production) and uncoupled oxidation (heat production) for both palmitate and pyruvate were measured in muscle biopsies from 40 children sustaining burns on more than 40% of their body surface area and from 13 healthy children controls. RESULTS: Maximal mitochondrial oxidation of pyruvate and palmitate were reduced in burn patients compared with controls (4.0 +/- .2:1.9 +/- .1 micromol O2/citrate synthase activity/mg protein/min pyruvate; control:burn; P < .001 and 3.0 +/- .1: .9 +/- .03 micromol O2/citrate synthase activity/mg protein/min palmityl CoA; control:burn; P = .003). Uncoupled oxidation was the same between groups. CONCLUSIONS: The maximal coupled mitochondrial oxidative capacity is severely impaired after burn injury, although there are no alterations in the rate of uncoupled oxidative capacity. It may be that the ratio of these indicates that a larger portion of energy production in trauma patients is wasted through uncoupling, rather than used for healing.

Insulin sensitivity is related to fat oxidation and protein kinase C activity in children with acute burn injury.

Impaired fatty acid oxidation occurs with type 2 diabetes and is associated with accumulations of intracellular lipids, which may increase diacylglycerol (DAG), stimulate protein kinase C activity, and inactivate insulin signaling. Glucose and fat metabolism are altered in burn patients, but have never been related to intracellular lipids or insulin signaling. Thirty children sustaining >40% total body surface area burns were studied acutely with glucose and palmitate tracer infusions and a hyper-insulinemic euglycemic clamp. Muscle triglyceride, DAG, fatty acyl CoA, and insulin signaling were measured. Liver and muscle triglyceride levels were measured with magnetic resonance spectroscopy. Muscle samples from healthy children were controls for DAG concentrations. Insulin sensitivity was reduced and correlated with whole body palmitate beta-oxidation (P = .004). Muscle insulin signaling was not stimulated by hyper-insulinemia. Tissue triglyceride concentrations and activated protein kinase C-beta were elevated, whereas the concentration of DAG was similar to the controls. Free fatty acid profiles of muscle triglyceride did not match DAG. Insulin resistance following burn injury is accompanied by decreased insulin signaling and increased protein kinase C-beta activation. The best metabolic predictor of insulin resistance in burned patients was palmitate oxidation.

Postburn trauma insulin resistance and fat metabolism.

Hyperglycemia and insulin resistance have long been recognized in severe burn patients. More recently, it has been observed that controlling hyperglycemia, or alleviating insulin resistance, is associated with improved outcomes. This has led to a renewed interest in the etiology of insulin resistance in this population. The postinjury hyperglycemic response appears to be associated with multiple metabolic abnormalities, such as elevated basal energy expenditure, increased protein catabolism, and, notably, significant alterations in fat metabolism. The synergy of all of the responses is not understood, although many studies have been conducted. In this article we will review the present understanding of the relationship between fat metabolism and insulin resistance posttrauma, and discuss some of the recent discoveries and potential therapeutic measures. We propose that the insulin resistance is likely related to the development of "ectopic" fat stores, i.e., triglyceride (TG) storage in sites such as the liver and muscle cells. Deposition of TG in ectopic sites is due to an increase in free fatty acid delivery secondary to catecholamine-induced lipolysis, in conjunction with decreased beta-oxidation within muscle and decreased hepatic secretion of fats. The resultant increases in intracellular TG or related lipid products may in turn contribute to alterations in insulin signaling.

Plasma triglycerides are not related to tissue lipids and insulin sensitivity in elderly following PPAR-alpha agonist treatment.

Increases in plasma lipids, tissue triglycerides and decreases in mitochondrial function have been linked to insulin resistance and aging. In animals, peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonists decrease plasma lipids, intramyocellular fat (IMCL) and liver fat (LFAT) and improve mitochondrial beta-oxidative function and insulin sensitivity, but the effects in elderly were not known. Insulin sensitivity was assessed with a 2-h oral glucose tolerance test, magnetic resonance spectroscopy was used to asses IMCL, LFAT and plasma lipids were measured before and after 6, 11 and 61 days of PPAR-alpha agonist (fenofibrate) administration in 19 elderly (age 70+/-1 years) volunteers. Volunteers were stratified into healthy (N=7) and insulin resistant (N=12) groups. The baseline insulin sensitivity index (8.1+/-1.2 vs. 3.8+/-0.5, healthy vs. insulin resistant; P<0.001) was significantly higher in the healthy group. Fenofibrate treatment induced significant reductions in plasma triglycerides (P<0.001) and total cholesterol (P<0.001) in both groups. Nonetheless, neither fasted free fatty acids, glucose, insulin, nor insulin sensitivity improved in either group (day 1 vs. day 61, 8.1+/-1.2 vs. 8.1+/-0.9, healthy; and 3.8+/-0.5 vs. 4.2+/-0.05, insulin resistant). Furthermore, there was no change in IMCL or LFAT. These results indicate that whereas fenofibrate significantly lowers plasma lipids it neither affects insulin sensitivity nor intracellular lipids in elderly.

Recovery of labeled CO2 from acetate in severely burned children.

The purpose of this study was to determine the fractional recovery rate of labeled CO(2) in the breath of severely burned children. This information is needed to perform tracer studies of substrate oxidation using carbon-labeled fatty acids. Nine children, ages 4-14 yr with massive burns participated in the study. All experiments were performed 7 days post burn after an overnight fast. A primed (60 micromol/kg), constant (2.0 micromol.kg(-1).min(-1)) infusion of [1,2-(13)C]acetate was given during a 4-h basal period and during a 4-h hyperinsulinemic euglycemic clamp. A priming dose (150 micromol/kg) of NaH(13)CO(3) was given at the beginning of the study. Breath samples were collected every 10 min during the last 40 min of each period. Indirect calorimetry was performed during the last 30 min of each period. The isotopic enrichment of (13)CO(2) was determined by isotope ratio-mass spectrometry, and total CO(2) excretion was measured by indirect calorimetry. The fractional recovery of acetate label was 0.89 +/- 0.05 and 0.88 +/- 0.04 during the basal state and clamp, respectively. We conclude that the fractional recovery of labeled acetate in severely burned children is approximately three times the recovery of a nonburned adult and similar to the value in exercising adults. The high recovery rate reflects the rapid turnover of the TCA cycle in burned children relative to the rate of exchange reactions. Minimal correction of expired CO(2) data is needed in this circumstance to quantify fatty acid oxidation using (13)C-labeled fatty acids.

Role of fat metabolism in burn trauma-induced skeletal muscle insulin resistance.

OBJECTIVE: Review current evidence on the role of fat in post-trauma insulin resistance, in reference to new studies with peroxisome proliferating activating receptor-alpha agonists. DESIGN: Review. SETTING: University laboratory. PATIENTS: Thirty pediatric burn trauma patients. INTERVENTIONS: Fourteen days of peroxisome proliferating activating receptor-alpha agonist immediately following burn trauma. MEASUREMENTS AND MAIN RESULTS: We measured glucose metabolism and fat metabolism via tracer methodology and intracellular measurements. Insulin-stimulated glucose uptake is impaired following burn trauma, as is intracellular insulin signaling, palmitate oxidation, and mitochondrial oxidative capacity. Furthermore, levels of intracellular lipids are increased. Two weeks of peroxisome proliferating activating receptor-alpha treatment significantly reverses these pathologic changes incurred from burn injury. CONCLUSIONS: Severe burn injury seriously affects multiple aspects of glucose and fat metabolism within the muscle, which can adversely affect clinical outcomes. Treatment with a peroxisome proliferating activating receptor-alpha drug may be a potential new therapeutic option.